Pulmonary hypertension is a disorder of the lung in which the pressure in the pulmonary artery (the blood vessel that leads from the heart to the lungs) rises above normal levels. If left untreated, pulmonary hypertension may become life threatening. Symptoms of pulmonary hypertension include shortness of breath with minimal exertion, fatigue, chest pain, dizzy spells fainting, and other symptoms. Pulmonary hypertension is frequently misdiagnosed and has often progressed to late stage by the time it is accurately diagnosed. Moreover, pulmonary hypertension has been historically chronic and incurable with a poor survival rate.
When pulmonary hypertension occurs in the absence of a known cause, it is referred to as primary pulmonary hypertension (PPH). There are many unknown causes of PPH.
When the cause of pulmonary hypertension is known, it is called secondary pulmonary hypertension (SPH). Common causes of SPH is the breathing disorders emphysema, bronchitis and chronic obstructive pulmonary disorder, among others. Other less frequent causes are the inflammatory or collagen vascular diseases such as scleroderma, CREST syndrome or systemic lupus erythematosus. Congenital heart diseases that cause shunting of extra blood through the lungs like ventricular and arterial septal defects, chronic pulmonary thromboembolism (old blood clots in the pulmonary artery), HIV infection, liver disease and diet drugs like fenfluramine and dexfenfluramine are also causes of pulmonary hypertension.
Angiotensin-converting enzyme inhibitors (ACEI) are drugs used to treat hypertension (high blood pressure) and congestive heart failure. These drugs are also used to alleviate the strain on hearts damaged from heart attacks. ACEIs block production of an enzyme that helps convert the protein angiotensin I into angiotensin II, a protein that makes blood vessels constrict and promotes retention of fluid in the body, thereby raising blood pressure. ACEIs also make blood vessels relax, which helps lower blood pressure and allows more oxygen-rich blood to reach the heart. Captorpirl (Capoten), Ramipril (Altace, and Enalipril (Vasoted) are commonly used ACE inhibitor.
Angiotensin receptor blockers (ARBs) (also referred to as angiotensin II receptor agonists) such as losartan (COZAAR®) and valsartan (DIOVAN®) reduce hypertension by displacing angiotensin II from receptors on the surface of cells. ARBs are used as alternatives to the less expensive ACEI inhibitors because they have fewer side effects.
Beta-adrenergic blocking agents, or beta-blockers, are used in the treatment of high blood pressure. Beta-blockers are also used to relieve angina (chest pain) and in heart attack patients to help prevent additional heart attacks. Beta-blockers are also used to correct irregular heartbeat, prevent migraine headaches, and treat tremors. Beta-blockers are competitive inhibitors and interfere with the action of stimulating hormones on beta-adrenergic receptors in the nervous system. Beta-blockers can be subdivided into two distinct groups, known as beta-1 and beta-2. Beta-1 blockers mainly affect the heart, and beta-2 blockers mainly affect receptors in bronchial tissue. Most beta-blockers are non-specific, i.e., they have both beta-1 and beta-2 effects.
Calcium-channel blockers are presently used to control hypertension, chest pain and irregular heartbeats. Calcium-channel blockers slow the rate at which calcium passes into the heart muscle and into the vessel walls, thereby relaxing the vessels. The relaxed vessels let blood flow more easily through them, thereby lowering blood pressure.
Vasodilators are medicines that act directly on muscles in blood vessel walls to make blood vessels widen (dilate). Vasodilators are used to treat high blood pressure. By widening the arteries, these drugs allow blood to flow through more easily, reducing blood pressure. Controlling high blood pressure is important because the condition puts a burden on the heart and the arteries, which can lead to permanent damage over time. If untreated, high blood pressure increases the risk of heart attacks, heart failure, stroke, or kidney failure. Examples of vasodilators include prostacyclin and its analogs.
It has been shown that vasodilators such as prostacyclin and prostacyclin analogs as well as calcium channel blockers such as diltiazem (CARDIZEM®) or nifedipine (PROCARDIA®) decrease pulmonary vascular resistance in some patients when administered systemically. For example, it has been found that continuous intravenous infusion of the vasodilator epoprostenol (FLOLAN®), or prostacyclin, improves exercise capacity, quality of life, hemodynamics and long-term survival in patients with primary pulmonary hypertension. Epoprostenol is a potent, short-acting vasodilator and inhibitor of platelet aggregation by vascular endothelium.
Continuous intravenous prostacyclin is far from ideal as a treatment for pulmonary hypertension, however, because the agent is available only in limited supply, it is very costly, and optimal management requires that the intravenous therapy with prostacyclin be started in specialized centers familiar with the technique, equipment, and dose ranging. Moreover, continuous intravenous administration of prostacyclin results in significant side effects in patients, including jaw pain, nausea, and anorexia, plus the inconvenience and potential danger from prolonged cathertization and breakdowns in the delivery system. Further, because the agent is delivered systemically with only a small percentage of the agent actually absorbed by the pulmonary system, it must be administered in high dosages.
Epoprostenol or the prostacyclin analog treprostinil sodium may be administered via injection to treat pulmonary hypertension. Delivery, however, is systemic and not localized to the lung. Thus, the drug must be administered in high doses, with only a small percentage actually reaching the lungs.
It has also been shown that calcium channel blockers may alleviate pulmonary vasoconstriction and prolong life in about 20 percent of patients with PPH. Rich S, Kaufmann E, Levy P S. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327:76-81, which is incorporated herein by reference. In patients who show evidence of an acute hemodynamic response, long-term treatment with calcium channel blockers administered orally can produce a sustained hemodynamic response and increase survival. However, oral administration does not produce a localized effect on the lungs and therefore high doses must be administered producing a systemic effect, perhaps unnecessarily. Moreover, oral administration in high dosages over an extended period of time may produce unwanted side-effects in some patients.
There is, therefore, a need for an improved method of treating hypertension.